Participant at FHI
An estimated 5 to 15% of the Norwegian population suffer from influenza annually. Seasonal influenza causes significant illness and health care resource use. The Norwegian Institute of Public Health (NIPH) reports that approximately 900 people die from influenza each year in Norway.
In order to reduce morbidity and mortality from influenza, the NIPH recommends seasonal influenza vaccination for particular risk groups, including children with chronic illness and impaired immunity against infection. The NIPH has requested a Health Technology Assessment of influenza vaccination of both chronically ill and healthy children. We will perform an HTA that includes a systematic review of the effect of influenza vaccination in these groups. If vaccinating chronically ill children is found to be effective, we will also perform a health economic evaluation.
The Norwegian Institute of Public Health (NIPH) has requested an updated systematic review of the literature on vaccine efficacy and a cost-effectiveness analysis. The mandate was discussed in a meeting, and the NIPH and the Norwegian Knowledge Centre for the Health Services (NOKC) agreed to focus on children in general and children in risk groups specifically.
To assess the clinical effect and cost-effectiveness of influenza vaccination of chronically ill and healthy children.
Seasonal influenza causes significant illness and health care resource use as 5 to 15% of the Norwegian population suffers from the disease annually. The Norwegian Institute of Public Health (NIPH) reports that approximately 900 people die from influenza each year (1). The annual average number of working days lost due to influenza has been estimated to 793 000, and the annual direct costs to USD 22 mill. (2).
In order to reduce the morbidity and mortality from influenza, the NIPH recommends seasonal vaccination of particular risk groups. Risk groups include those at high risk of developing severe disease, such as children and adults with chronic illness and impaired immunity against infection, adults older than 65 year and residents at institutional care facilities (1). In addition, NIPH recommends seasonal vaccination to those with increased risk of exposure to the influenza virus, such as health care workers. Annual vaccination is recommended since the World Health Organization (WHO) revises its advice about which strains to include in the vaccine on an annual basis. WHO recommendations are based on data from a global influenza surveillance and response system (GISRS). The reported efficacy/effectiveness of influenza vaccines will vary from one year to another, depending on the match between the vaccine strains and prevailing influenza strains (3).
NIPH reports that nearly 1 million people in Norway belong to one or more risk groups (1), but only 400 000 doses of influenza vaccine are distributed each year (4). The Norwegian Institute of Public Health (NIPH) requested a systematic review of vaccine efficacy in children with chronic disease in order to strengthen their advice to this population group. It is necessary to include studies on healthy children in the analysis in order to complement the body of evidence.
Because the influenza vaccine is not currently reimbursed in Norway families of children in risk groups must cover vaccine costs which could be a barrier to achieving high vaccine coverage among these children. The NIPH believes that free vaccination is an important tool to achieve this and might also promote equity in this matter. The NIPH has therefore requested a health technology assessment to ascertain the potential effect and cost-effectiveness of free vaccination of high risk children in Norway.
We will perform a Health Technology Assessment (HTA) consisting of a systematic review of clinical effectiveness and a health economic evaluation. The HTA will be performed in accordance with the guidelines for Norwegian HTA reports (Handbook).
We will search for and include systematic reviews following this PICO:
Chronically ill children and children up to 18
Annual influenza vaccine
No intervention/no influenza vaccine/other vaccination
Morbidity due to influenza (i.e. pneumonia)
Admission to hospital
Influenza (laboratory confirmed)
Worsening of chronic disease (as defined in the original articles)
Parents or caregivers absence from work
Serious adverse events
Systematic reviews and HTA reports of high methodological quality
No language restrictions will be applied during the literature search, but we will only include reviews written in English or in one of the Scandinavian languages.
We will search for systematic reviews and HTA reports by combining selected index terms and free text terms comprising influenza and vaccines. We will apply a methodological search filter for systematic reviews.
We will include systematic reviews that are of high methodological quality (using the assessment criteria described in the Handbook for the Norwegian Knowledge Centre for the Health Services) and fulfill our inclusion criteria.
If we identify more than one systematic review of high methodological quality that fulfils our inclusion criteria and present results for the same outcomes, we will include the most up-to-date review. If necessary (i.e., a review with literature search more than two years old), we will consider preparing our own systematic review that combines the studies from the included review with primary studies published after the date of the review’s literature search. If we do not identify any relevant reviews of high methodological quality, we will consider performing our own systematic review based on the PICO described above. If we decide to prepare our own systematic review, we will limit the study design to randomized controlled trials.
Selection of systematic reviews
The review authors will work independently and in pairs to review all references generated by the search to identify potentially relevant publications based on title and/or abstract. We will retrieve full text of all potentially eligible references and work independently and in pairs to assess whether these references should be included according to the inclusion criteria. We will resolve disagreements by discussion or, if required, by consulting a third person.
Assessment of methodological quality
Potentially relevant systematic reviews meeting the predefined inclusion criteria will be assessed for methodological quality according to the Handbook for the Norwegian Knowledge Centre. All assessments will be performed and agreed upon by two of the review authors working independently. We will resolve disagreements by discussion or, if required, by consulting one of the other review authors.
Data extraction and management
One review author will extract data from the included references and another review author will verify the data.
We will capture the following data: Identification details of the systematic reviews and the included studies (authors, year of publication, date for literature search, study design, methodological quality of included studies, setting and funding); Participant characteristics (gender, age, chronic illness); Intervention and control characteristics (type of vaccine); Outcomes (outcome data [results], methods for assessing/measuring the outcome data, length of follow-up, loss to follow-up).
We will extract outcome data from the systematic reviews and present the results in GRADE evidence profile, summary of findings tables (see below for more details). We will also present forest plots from the systematic reviews when available. If any data need to be re-analyzed, we will enter and analyze the data using the Review Manager software (RevMan). If appropriate according to population, intervention and outcome, we will perform meta-analyses using a “random effects model”. For dichotomous outcomes, we will calculate risk ratios (RR) and for continuous outcomes, we will express the effect size as mean differences (MD) where possible. For all outcomes, we will, as far as possible, conduct each analysis according to the “intention-to-treat” principle. If the outcome data cannot be pooled in meta-analyses, we will describe the results in a narrative form. Planned subgroup analyses will be made; i.e. age-related and separate analyses within the different chronic disease groups.
Grading the quality of evidence
Two review authors will assess the overall quality of evidence for each outcome using GRADE (Grading of Recommendations Assessment, Development, and Evaluation). GRADE provides criteria for rating the quality of evidence considering study design, risk of bias, imprecision, inconsistency, indirectness, publication bias, large magnitude of effect, dose response gradient and confounding factors. We will follow the GRADE guidelines and categorize our confidence in the effect estimates into four levels: high, moderate, low and very low. We will present both the results from the meta-analyses (the estimate of effect) and the quality rating in ”Summary of Findings” tables prepared using the guideline development tool (GDT), http://www.guidelinedevelopment.org/. For more details about the GRADE method, we refer to publications by the GRADE Working group (www.gradeworkinggroup.org).
Two internal researchers and one (protocol) or two (final report) external clinical experts will review the protocol as well as the final report.
If the systematic review reveals that the vaccine is effective for chronically ill children, we will conduct an economic evaluation.
In order to estimate the long-term consequences of possible complications from influenza we will construct a Markov-model. We will use efficacy data and side effects summarized within the project, and Norwegian epidemiological data. We will search for inputs to the health economic model, including health-related quality of life weights and costs. The model will be probabilistic, that is, probability distributions will characterize parameters that are uncertain. The probability distributions will represent the degree of uncertainty relating to these parameters.
Chronically ill children up to 18
Annual influenza vaccine
No intervention/no influenza vaccine/other vaccine
Cost per QALY, cost per life year, net health benefit, probability of being cost-effective, value of information analysis
Health care and societal